1. health and fitness
2. disease
3. asthma

Eur Respir J 2008; 32: 1096–1110
DOI: 10.1183/09031936.00002108
CopyrightßERS Journals Ltd 2008
ERS TASK FORCE
Definition, assessment and treatment of
wheezing disorders in preschool children:
an evidence-based approach
P.L.P. Brand, E. Baraldi, H. Bisgaard, A.L. Boner, J.A. Castro-Rodriguez, A. Custovic,
J. de Blic, J.C. de Jongste, E. Eber, M.L. Everard, U. Frey, M. Gappa,
L. Garcia-Marcos, J. Grigg, W. Lenney, P. Le Souëf, S. McKenzie, P.J.F.M. Merkus,
F. Midulla, J.Y. Paton, G. Piacentini, P. Pohunek, G.A. Rossi, P. Seddon,
M. Silverman, P.D. Sly, S. Stick, A. Valiulis, W.M.C. van Aalderen, J.H. Wildhaber,
G. Wennergren, N. Wilson, Z. Zivkovic and A. Bush
ABSTRACT: There is poor agreement on definitions of different phenotypes of preschool
wheezing disorders. The present Task Force proposes to use the terms episodic (viral) wheeze to
describe children who wheeze intermittently and are well between episodes, and multiple-trigger
wheeze for children who wheeze both during and outside discrete episodes. Investigations are
only needed when in doubt about the diagnosis.
Based on the limited evidence available, inhaled short-acting b2-agonists by metered-dose
inhaler/spacer combination are recommended for symptomatic relief. Educating parents
regarding causative factors and treatment is useful. Exposure to tobacco smoke should be
avoided; allergen avoidance may be considered when sensitisation has been established.
Maintenance treatment with inhaled corticosteroids is recommended for multiple-trigger wheeze;
benefits are often small. Montelukast is recommended for the treatment of episodic (viral) wheeze
and can be started when symptoms of a viral cold develop.
Given the large overlap in phenotypes, and the fact that patients can move from one phenotype
to another, inhaled corticosteroids and montelukast may be considered on a trial basis in almost
any preschool child with recurrent wheeze, but should be discontinued if there is no clear clinical
benefit.
Large well-designed randomised controlled trials with clear descriptions of patients are needed
to improve the present recommendations on the treatment of these common syndromes.
KEYWORDS: Asthma, episodic viral wheeze, inhaled corticosteroids, montelukast, multipletrigger wheeze
CONTENTS
Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Definitions of temporal pattern of wheeze . . . . . . . . . . . . . . . . . . . . . . . . .
Retrospective epidemiological description of duration of wheeze . . . . . . . . .
Long-term outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Recommendations: definitions of phenotypes (based on low-level evidence)
Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
History and physical examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Recommendations: assessment (based on very low-level evidence) . . . . . .
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AFFILIATIONS
For affiliation details, please see the
Acknowledgements section.
CORRESPONDENCE
P.L.P. Brand
Princess Amalia Children’s Clinic
Isala klinieken
P.O. Box 10400
8000 K Zwolle
The Netherlands
Fax: 31 384247660
E-mail: p.l.p.brand@isala.nl
Received:
January 06 2008
Accepted after revision:
May 26 2008
STATEMENT OF INTEREST
Statements of interest for
P.L.P. Brand, E. Baraldi, H. Bisgaard,
A.L. Boner, J.A. Castro-Rodriguez,
A. Custovic, J.C. de Jongste, E. Eber,
M.L. Everard, U. Frey, M. Gappa,
L. Garcia-Marcos, W. Lenney,
S. McKenzie, G. Piacentini,
G.A. Rossi, P. Seddon, M. Silverman,
A. Valiulis, W.M.C. van Aalderen,
J.H. Wildhaber, G. Wennergren and
A. Bush can be found at
www.erj.ersjournals.com/misc/
statements.shtml
European Respiratory Journal
Print ISSN 0903-1936
Online ISSN 1399-3003
EUROPEAN RESPIRATORY JOURNAL
P.L.P. BRAND ET AL.
Treatment . . . . . . . . . . . . . . .
Environmental manipulation .
Parent and patient education
Pharmacological therapy . . .
Delivery devices . . . . . . . . . .
WHEEZING DISORDERS IN PRESCHOOL CHILDREN
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1101
1101
1101
1102
1104
Methodological considerations . . . . . . . . . . . . . . . . . 1104
Recommendations for treatment (based on low-level evidence
unless otherwise specified) . . . . . . . . . . . . . . . . . . . . 1104
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1106
opulation studies have shown that approximately one
in three children has at least one episode of wheezing
prior to their third birthday, and the cumulative
prevalence of wheeze is almost 50% at the age of 6 yrs [1, 2].
Most wheeze in preschool children is associated with viral
upper respiratory tract infections, which recur frequently in
this age group. As a result, recurrent wheeze is a very common
clinical problem facing practitioners throughout the world. It
has been estimated that the problem of preschool wheeze
utilises 0.15% of the total healthcare budget in the UK [3].
Despite its high prevalence, there is a lack of evidence
regarding the pathophysiology and treatment of preschool
wheeze.
The details of the search strategies are available on request.
In most cases, the results were limited to English language
material. No date limits were applied.
P
The understanding of preschool wheezing illness has been
enhanced by a number of birth cohort studies, in particular by
highlighting the existence of different phenotypes [1, 4, 5].
However, the possible implications of these different phenotypes for treatment are poorly acknowledged in current
international guidelines on the diagnosis and management of
asthma [6–8]. Indeed, although two paediatric societies recently
published guidelines on preschool wheezing disorders [9, 10],
comprehensive evidence-based guidelines on the diagnosis and
management of wheezing disorders in preschool children have
not been published to date. The present ERS Task Force was
instituted for exactly that purpose. The Task Force defined a
phenotype as a cluster of associated features that are useful in
some way, such as in managing the child or understanding the
mechanisms of disease. Given the multifactorial nature of all
wheezing disorders (including asthma) in general, and preschool wheezing disorders in particular, it is highly likely that
clinical phenotypes described in the literature are the extremes
of a broad spectrum of wheezing disorders [11, 12]. The Task
Force therefore realises that the phenotypes defined in the
present report are not exhaustive, and that many individual
patients may not fit into the categories described. There may be
overlap between phenotypes and they may change over time.
Each subgroup, consisting of at least three people, reviewed the
retrieved references for relevant papers, adding additional
papers from personal files if required. The evidence from the
retrieved relevant papers was graded, according to recent
recommendations [13], as high-, moderate-, low- or very lowgrade evidence based on the following criteria: study design
and quality (systematic reviews and randomised controlled
trials: high quality; observational studies: low quality; any other
type of article: very low quality), consistency of the data and
relevance. A draft report was prepared by each subgroup. This
was submitted to the whole Task Force for comments. The
individual reports were then combined by the Task Force chairs
(P.L.P. Brand and A. Bush), and the present manuscript was
organised into three main sections: Definitions, Assessment and
Treatment. Based on the evidence reviewed and graded by each
subgroup, the Task Force chairs put together a list of
recommendations that were graded according to the Grading
of Recommendations Assessment, Development and Evaluation
(GRADE) methodology [13]. Instead of the usual system of
grading the strength of recommendations as A, B, C or D, the
GRADE working group proposal to use a different, and more
readily interpretable, system of categorising recommendations
in four groups was followed: should (or should not) be done, or
possibly should (or should not) be done. Recommendations
could only be categorised as should (or should not) be done
when the entire Task Force unanimously endorsed this
recommendation.
The purpose of the present Task Force was to produce
guidelines for the treatment of wheezing in children aged
,6 yrs based on all of the available evidence.
RESULTS
One of the main findings of the present Task Force was that the
evidence on which to base recommendations is limited in this
age group. When no evidence was available from original
studies, narrative reviews and published expert opinions were
considered for inclusion in the present report. All of the
evidence presented is of low quality unless specifically stated
otherwise. The present recommendations are likely to change
when more evidence becomes available.
METHODS
Literature searches were performed in order to identify
material relating to preschool wheeze. Eleven relevant study
areas were identified, and, for each area, a literature search
was carried out based on a predefined series of key clinical
questions and keywords by a single clinical librarian. Search
strategies were constructed by the clinical librarian in
collaboration with a representative of each group in the Task
Force. Searching included the Cochrane library, PubMed and
EMBASE, and the strategies included filters to limit the results
by study type (reviews, randomised controlled trials and other
types of experimental research) and age range (0–5 yrs).
DEFINITIONS
Definitions used in children aged ,6 yrs are often confusing.
Although many individuals later diagnosed with asthma
exhibit their first symptoms during the preschool age period,
making a diagnosis of asthma in preschool children is difficult.
According to the latest edition of the Global Initiative for
Asthma (GINA) guidelines, asthma is a syndrome with a
highly variable clinical spectrum, characterised by airway
inflammation [6]. Inflammation, however, has been poorly
studied in preschool children, and may be absent in very
young children who wheeze [14]. Therefore, a symptoms-only
descriptive approach, outlined in table 1, was adopted.
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The majority of the Task Force agreed not to use the term
asthma to describe preschool wheezing illness since there is
insufficient evidence showing that the pathophysiology of
preschool wheezing illness is similar to that of asthma in older
children and adults.
Wheeze is defined as a continuous high-pitched sound with
musical quality emitting from the chest during expiration. It is
one of a number of forms of noisy breathing in preschool
children [15]. Parents differ widely in their understanding and
definition of wheeze; some think it is a sound such as
whistling, squeaking or gasping, whereas others define it as
a different rate or style of breathing, or think it is the same as
cough [15–19]. If based on parental report alone, therefore,
children may be labelled as having wheeze when they do not.
If possible, therefore, wheeze should be confirmed by a health
professional, bearing in mind that not all healthcare workers
are equally accurate in estimating the severity of wheeze [20].
By definition, the present Task Force has not addressed the
clinical problem of isolated cough without wheeze. Guidelines
on the diagnosis and management of chronic cough in
childhood are available elsewhere [21]. Since wheeze is the
end result of narrowing of intrathoracic airways and expiratory flow limitation, irrespective of the underlying mechanism,
there are numerous reasons for a child to wheeze, including
anatomical abnormalities of the airways, cystic fibrosis and
bronchomalacia. The Task Force unanimously agreed that the
differential diagnosis of wheeze in preschool children should
not be discussed in detail in the present report for a number of
reasons. First, there is very little, if any, evidence to support
recommendations regarding the diagnostic approach to a
wheezing infant. Secondly, the differential diagnosis of wheeze
in preschool children has been discussed in detail in textbooks
[22, 23]. Thirdly, it was felt that most clinicians and researchers
would recognise the clinical problem of recurrent wheezing in
preschool children without an in-depth discussion of its
differential diagnosis.
TABLE 1
P.L.P. BRAND ET AL.
Causative factors for recurrent wheeze may vary from child to
child and within a child over time, due to a large number of
interactions between genetic factors and the environment [24]. As
in adults [25], specific combinations of genetic and environmental
factors determine the individual patient’s phenotype. In clinical
practice, however, most of these factors are unknown.
The phenotypes used in epidemiological studies (transient
versus persistent wheeze) can only be applied retrospectively
[1, 4, 5]. Although the use of these phenotypes has improved
mechanistic understanding, they are of little use to the
clinician. Although the epidemiological phenotype of transient
wheeze is often assumed to be equivalent to the clinical
phenotype of episodic wheeze, this has never been demonstrated. Therefore, definitions of temporal pattern of wheeze
(which are useful to clinicians) were distinguished from the
retrospective definitions of duration of wheeze (which are
used in epidemiological studies; table 1).
Definitions of temporal pattern of wheeze
Episodic (viral) wheeze
Episodic (viral) wheeze is defined as wheeze in discrete
episodes, with the child being well between episodes.
Although not unique to the preschool age group [26, 27], this
phenotype appears to be most common in preschool children
[1, 4, 5]. It is usually associated with clinical evidence of a viral
respiratory tract infection, although microbiological diagnostic
studies are rarely performed in clinical practice. The most
common causative agents include rhinovirus, respiratory
syncytial virus (RSV), coronavirus, human metapneumovirus,
parainfluenza virus and adenovirus [28]. Repeated episodes
tend to occur seasonally.
Factors underlying the frequency and severity of episodes are
only partially understood, but the severity of the first episode
(which is, in turn, related to pre-existent impaired lung
function and younger age), atopy, prematurity and exposure
to tobacco smoke have been implicated [29–35]. Whether or not
Definitions used in the present report
Term
Definition
Temporal pattern of wheeze
Episodic (viral) wheeze
Wheezing during discrete time periods, often in
association with clinical evidence of a viral cold,
with absence of wheeze between episodes
Multiple-trigger wheeze
Wheezing that shows discrete exacerbations,
but also symptoms between episodes
Duration of wheeze
Transient wheeze
Symptoms that commenced before the age of
3 yrs and are found (retrospectively) to have disappeared
by the age of 6 yrs; transient wheeze may be episodic
or multiple-trigger wheeze
Persistent wheeze
Symptoms that are found (retrospectively) to have
continued until the age of o6 yrs; persistent wheeze may
be episodic or multiple-trigger wheeze
Late-onset wheeze
Symptoms that start after the age of 3 yrs;
late-onset wheeze may be episodic
or multiple-trigger wheeze
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P.L.P. BRAND ET AL.
the initial episode is classified as bronchiolitis is irrelevant.
Similarly, it is not known whether or not the causative agent of
the initial episode plays a major role in determining long-term
outcome. Both RSV and rhinovirus have been linked to an
increased risk of persistent wheezing over time [36–38]. In the
case of RSV, most studies show that this has disappeared by
the age of 11 yrs, and is not associated with an increased risk of
atopy [37]. For rhinovirus, such long-term data are lacking.
Episodic (viral) wheeze most commonly declines over time,
disappearing by the age of 6 yrs, but can continue as episodic
wheeze into school age, change into multiple-trigger wheeze or
disappear at an older age [1, 26].
Multiple-trigger wheeze
Although a viral respiratory tract infection is the most common
trigger factor for wheeze in preschool children, some young
children also wheeze in response to other triggers (multipletrigger wheeze; table 1). Others have used the term persistent
wheeze for this syndrome, but this is confusing because this
term is also used to describe the long-term temporal outcome
of wheeze (discussed further later).
Systematic studies of other such triggers are lacking. A textbook,
written by two experts in the field, suggests that tobacco smoke
and allergen exposure are important triggers, and that some
children may also wheeze in response to mist, crying, laughter or
exercise [23]. Although many believe that multiple-trigger
wheeze in preschool children reflects chronic allergic airway
inflammation (and could, therefore, be classified as asthma),
there is little evidence to support this (see Investigations section).
Retrospective epidemiological description of duration of
wheeze
The outcome and related characteristics of preschool wheeze
have been determined by prospective birth cohort studies;
however, in individuals, these categories can only be recognised retrospectively [1, 4, 5]. Therefore, these phenotypes can
only be used in epidemiological studies and are of no value in
clinical practice. Three groups have been recognised (table 1)
but it should be stressed that the overlap between these groups
is considerable and that the age limits applied are arbitrary.
In the Tucson birth cohort, 34% of children wheezed during the
first 3 yrs of life but 60% of these had ceased to wheeze by the
age of 6 yrs. As a group, these infants with transient wheeze
show reduced lung function prior to the first respiratory
illness, are exposed to maternal smoking, and are not
characterised by a personal history of eczema or a family
history of asthma [1]. In an attempt to predict which preschool
wheezers continue to wheeze beyond the age of 6 yrs, these
history data have been combined with characteristics such as
blood eosinophilia into an asthma predictive index [39].
Although groups of children with a positive asthma predictive
index respond to inhaled corticosteroid (ICS) therapy [40, 41],
the predictive value of this index for the disappearance or
persistence of wheeze over time in individual patients is of
only modest clinical value [39].
WHEEZING DISORDERS IN PRESCHOOL CHILDREN
to be atopic and show normal lung function at birth and through
the teenage years [42].
Children who wheezed in the first 3 yrs and continued beyond
the age of 6 yrs were termed persistent wheezers [1]. This was
associated with normal lung function during the first year of
life, but reduced lung function from the preschool age period
and through adulthood (in most but not all cohort studies),
with atopy and a family history of asthma [1, 4, 5].
Long-term outcome
Long-term studies have shown that ,25% of children with
persistent asthma had started to wheeze by the age of
6 months and 75% by the age of 3 yrs [1, 4, 5, 43]. Although
the long-term outcome of asthma in school-age children has
been extensively studied, both at the general population level
and in patients with more severe disease, little evidence
regarding the outcome of preschool wheezing into adulthood
is available. Ongoing birth cohort studies should be able to
provide information on the outcome in general populations
during the 2010s. Considering more severe early wheeze, half
of the children hospitalised with acute wheeze before the age
of 2 yrs were symptom-free by the age of 5 yrs and 70% by
10 yrs, but only 57% by 17–20 yrs [44–46], illustrating the
tendency for relapse during adolescence. Female sex, passive
smoking during infancy and early sensitisation to allergens
were risk factors for symptoms continuing into early adulthood, but type of virus and premature birth were not.
Recommendations: definitions of phenotypes (based on
low-level evidence)
1) For clinical purposes, wheeze should be described in terms
of its temporal pattern and classified as episodic (viral) or
multiple-trigger wheeze.
2) Use of the terms transient, late-onset and persistent wheeze
should probably be limited to population-based cohort studies
and should not be used clinically.
3) The term asthma should probably not be used in preschool
children because data regarding underlying inflammation are
lacking.
ASSESSMENT
History and physical examination
The purpose of history-taking and physical examination is to
confirm that the preschool child has a wheezing disorder, to
identify the pattern of symptoms, the severity of the condition
and any possible trigger factors, and to look for features
suggestive of another diagnosis or associated condition. The
detailed diagnostic tests for these conditions are beyond the scope
of the present report and have been discussed by others [23].
The 15% of children who started wheezing after the age of 3 yrs
and were still wheezing at the age of 6 yrs were defined as
having late-onset wheeze. This was associated with maternal
asthma, male sex and a history of rhinitis [1]. This group tended
History
History-taking is the main diagnostic instrument in the
assessment of preschool wheeze in those who are not
wheezing during the consultation. Accurately identifying
wheeze from the history can be difficult since the term is used
by parents and healthcare workers to describe a variety of
symptoms [15, 17–19]. Children with doctor-confirmed wheeze
exhibit greater airways resistance than children with only
reported wheeze [47], even though interobserver agreement
between doctors is poor [48]. A video questionnaire may help
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parents to distinguish wheeze from upper airway noises [49].
Symptom scoring systems have been insufficiently validated to
justify general use, and validated questionnaires for this
purpose in this particular age group are needed. Noisy
breathing is common among infants aged ,6 months but only
a small proportion have wheeze [15]. Reported noisy breathing
that responds to bronchodilator therapy is likely to be genuine
wheeze and to be caused, at least in part, by constriction of
airway smooth muscle [50].
Physical examination
No evidence is available regarding the usefulness of physical
examination in wheeze assessment. A textbook states that the
degree of airway narrowing can only be estimated crudely and
indirectly, by assessing work of breathing (chest retractions,
nasal flaring and use of accessory respiratory muscles) and by
auscultation of the chest to assess the ratio of expiration to
inspiration and the degree of wheeze [23]. Upper airway
obstruction (in particular, nasal congestion) can contribute to
respiratory distress. The aim of further physical examination is
the identification of unusual or atypical features that would
suggest another underlying condition [23].
Investigations
The diagnosis of a preschool wheezing disorder can be made
by history-taking alone. The type, invasiveness and number of
any investigation largely depends upon the degree of
morbidity and the doubt about the diagnosis [23]. This is a
matter of clinical judgement. Most clinicians would agree that
investigations are only justified when symptoms are present
from birth, airway obstruction is abnormally severe, recovery
is very slow or incomplete (resulting in prolonged or repeated
hospital admission in the first few years of life), episodes
continue in the absence of a viral infection or, sometimes, in
cases when parents are very anxious [22, 23]. There is little
research evidence to guide the choice of investigations. Among
infants and preschool children with severe persistent symptoms who were investigated according to a fixed diagnostic
protocol, a considerable number of pathological findings were
observed suggesting that invasive investigations are justified
in this category [51, 52].
Microbiological investigations
With current viral culture and PCR technology, a wide range of
respiratory viruses can be identified, including the most
common causative viruses [28]. There is no evidence, however,
that this contributes to management, either in the short term
(the acute episode) or in the long term, and it is recommended
only for research purposes.
Tests of sensitisation to allergens
The reported prevalence of sensitisation in preschool children
with wheeze in population studies varies widely [1, 4, 5].
Limited evidence is available regarding the prevalence of
sensitisation in preschool children presenting to healthcare
workers with wheeze. One study comparing children aged 2–
5 yrs with doctor-confirmed wheeze who were responding
favourably to a bronchodilator to healthy non-wheezing
children found that 32% of wheezy children gave positive
skin-prick test results to one or more aeroallergens, compared
to 11% of healthy children (likelihood ratio 2.9) [53].
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Sensitisation to inhalant allergens in 1–4-yr-old children from
general practice increases the likelihood of the presence of
asthma at the age of 6 yrs by a factor of two to three [54].
Sensitisation to hen’s egg at the age of 1 yr is a reasonable
marker for allergic sensitisation to aeroallergens at the age of
3 yrs, with a specificity of .90% and sensitivity of .30% [55].
Total serum immunoglobulin E measurements in early life are
not predictive of outcome [56]. Although elevated eosinophilic
cationic protein levels in preschool wheezers are associated
with symptom persistence [57], the degree of overlap between
groups renders such measurements useless for clinical
purposes. Blood eosinophilia can be used as part of an asthma
predictive index, but the predictive value of this index (in
particular, that of a positive result) is low [39].
Radiological examinations
There is no evidence that chest radiographs help in the
diagnosis or treatment of preschool children with acute or
recurrent wheezing [58]. Improvements in diagnostic imaging
techniques may improve understanding of the mechanisms
and long-term outcome of early childhood wheezing disorders
by providing details about airway structure, airway wall
thickness and airway calibre. At present, however, specialised
imaging should be restricted to unusual or severe disease [22].
Measurement of gastro-oesophageal reflux
Although gastro-oesophageal reflux is common among infants
and preschool children with chronic or recurrent respiratory
symptoms [59], a beneficial effect of demonstrating and
treating gastro-oesophageal reflux in infants with wheeze has
not been shown.
Lung function tests
Studies have shown reduced forced expiratory flows associated with wheeze [50, 52, 60, 61]. Low lung function in
school-age children [62–64] and infants [65] appears to track
into early adulthood. It is not known, therefore, whether lung
function deficits in school-age children with wheezing reflect
developmental characteristics of the lung and airways in
wheezy children, disease activity while symptomatic or
remodelling secondary to airway inflammation. The presence
of airway reactivity in infancy is associated with lower
childhood lung function and increased risk of asthma in later
childhood [66], but the mechanisms of airway reactivity in this
age group are poorly understood and probably include factors
other than inflammation [67].
There are no studies supporting the usefulness of pulmonary
function tests in children with nonspecific symptoms, or in
distinguishing between episodic and multiple-trigger wheeze.
In the individual patient, however, determination of lung
function (and bronchodilator response) in preschool children
can help in the discrimination of common wheezing disorders
from other conditions [68, 69].
Exhaled nitric oxide and other assessments of airways
inflammation
Elevated exhaled nitric oxide fractions (FeNO) have been found in
wheezing infants, especially when they are atopic [70, 71], and
these normalise during treatment with ICSs [72] and montelukast
[73, 74]. FeNO in infants are affected by environmental exposures
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and genetic predisposition to atopy [75]. Reference values for
FeNO are only available for children aged o4 yrs [76]. For
uncooperative children aged ,4 yrs, measurement of FeNO has
not been standardised and there is no evidence supporting the
usefulness of measuring or monitoring FeNO in this age group.
Other tests of inflammation, such as analysis of induced sputum,
have not been studied at all in preschool children.
Airway wall biopsy and bronchoalveolar lavage
Few studies have applied bronchoalveolar lavage or bronchial
biopsy in preschool wheezing disorders. Most such investigations have been performed in children with severe or unusual
clinical features, limiting the generalisability of findings. Both
the degree of inflammation and the composition of the infiltrate
have been variable, with neutrophils dominating in some
studies, eosinophils in others and no evidence of either in
others [77]. The only consistent finding was thickening of the
reticular basement membrane in wheezy children [77], but not
in infants (median age 12 months), even when reversible airflow
obstruction and atopy were demonstrated [14]. A recent study
showed that, by a median age of 29 months, some children with
confirmed wheeze exhibit eosinophilic airway inflammation
and reticular basement membrane thickening, implying an age
window at 12–30 months during which interventions aimed at
preventing established airway inflammation might be possible
[78]. Further studies of airway inflammation using bronchoalveolar lavage and bronchial biopsy in large groups of
representative patients with episodic and multiple-trigger
wheeze are urgently needed in order to improve understanding
of the pathophysiology of preschool wheezing disorders.
Unfortunately, such studies are hindered by ethical and
practical constraints. At present, such invasive investigations
should only be used in unusual cases in specialised centres.
Recommendations: assessment (based on very low-level
evidence)
1) The pattern and triggers of wheeze, personal and family
history of atopy, and household smoking should be assessed
by history-taking.
2) Parentally reported wheeze should be confirmed by a health
professional whenever possible.
3) Tests of allergic sensitisation should be performed in
patients requiring long-term treatment and follow-up.
4) Other investigations should probably not be carried out
unless wheeze is unusually severe, therapy-resistant or
accompanied by unusual clinical features.
WHEEZING DISORDERS IN PRESCHOOL CHILDREN
using environmental control in the treatment of preschool age
wheezing to reduce existing symptoms (secondary prevention)
is the notion that allergen exposure contributes to the severity of
symptoms [80]. There is some evidence that exposure to
allergens in early life increases the risk of wheezing, but this is
dependent upon the allergen, the population and other
environmental factors [81]. The combination of sensitisation
and high exposure to sensitising allergen in early life is
associated with significantly poorer lung function at the age of
3 yrs [82]. Sensitisation to perennial allergens during the first
3 yrs of life is associated with reduced lung function at school
age, with concomitant high exposure to perennial allergens
early in life aggravating this [83]. High allergen exposure during
preschool age enhances the development of airway hyperresponsiveness in sensitised children with wheeze (with later-life
sensitisation and exposure having much weaker effects) [83].
Moving school-age atopic asthmatic children from their homes
to the low-allergen environment of high-altitude sanatoria
temporarily improves levels of markers of airway inflammation and asthma severity [84]. Some studies suggest that
allergen avoidance at home may also be of some benefit
amongst children of this age range [85, 86]. It remains unclear,
however, whether the required major reduction in exposure
can be achieved in normal life and whether it would be of
beneficial effect in young children since no studies on the
effects of allergen avoidance have been performed in preschool
children with wheeze [87].
Parent and patient education
Parental knowledge and understanding of wheezing disorders
in preschool children and their treatment is often inadequate
(especially with respect to medication and the preceding signs
and preventive actions) [88]; however, few educational studies
in wheezy children have explicitly focused on the preschool
age group.
Many educational studies have included children aged as
young as 2 yrs, but the age range of the study group is
frequently not described, and there is rarely an analysis of
whether outcomes are different in younger children. For
example, the Cochrane Review on educational interventions in
children and adolescents aged 2–18 yrs with asthma included
no separate analysis of outcomes in younger children [89].
Indeed, of the 32 studies included in the review, only one
studied preschool children exclusively [90]; two other studies
that included children aged ,2 yrs were excluded.
Allergen avoidance
Allergen avoidance to prevent the development of symptoms, in
either the population as a whole or high-risk subgroups
(primary prevention), is not discussed here. The rationale for
Of the few studies in preschool children, those that have
utilised multiple teaching sessions have shown improvements
in morbidity, with more symptom-free days and better
caregiver quality of life [90, 91], as well as improved knowledge and improved self-efficacy [92], and outcomes similar to
those in older children. These studies all used different
formats: reading of a home booklet followed by practitioner
review on next consultation [92], small group teaching by
nurses [90] and home-based education [91]. One other large
randomised controlled trial in preschool children with acute
wheeze found no effect of an education programme upon
subsequent healthcare utilisation, disability score, parent’s
quality of life and parental knowledge of asthma [93]. This
study included two structured 20-min one-to-one sessions, the
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TREATMENT
Environmental manipulation
Reducing tobacco smoke exposure
There is consistent strong evidence that passive exposure to
environmental tobacco smoke is harmful, in terms of both
induction and exacerbation of preschool wheeze [79], and
should be firmly discouraged.
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first during hospital attendance and the other 1 month later.
This raises the possibility that multiple educational sessions of
longer duration might be more effective in preschool children.
Virtually all studies in preschool children have targeted
education at parents or carers. However, young children
themselves may benefit from asthma education and practical
training in skills. One study found that children aged 2–5 yrs
who were exposed to a developmentally appropriate educational intervention that included a picture book and video tape
showed improved asthma knowledge, as well as better
compliance and health, compared to controls [94].
Therefore, although educating parents of preschool children
with wheeze (and perhaps also the children themselves)
appears effective, and is advised, more work is needed before
specific educational approaches can be recommended.
Pharmacological therapy
Short-acting b2-agonists
Inhaled rapidly acting b2-agonists are the most effective
bronchodilators available, and, therefore, the drugs of choice
for acute symptoms of wheeze. Double-blind placebo-controlled studies have demonstrated significant bronchodilatory
effects [95–98] and protective effects against bronchoconstrictor agents [99, 100] in infants and preschool children treated
with rapidly acting inhaled b2-agonist. Thus, infants possess
functional b2-receptors from birth, and stimulation of these
receptors can produce the same effects as in older children,
although paradoxical responses to inhaled b2-agonists have
been reported in infants [50, 101]. Oral administration of b2agonist is also effective but is limited by systemic side-effects
[102]. Intravenous infusion of b2-agonists has only shown an
advantage over hourly inhaled treatment in very severe acute
wheeze in young children [103].
After inhalation, b2-agonists are usually well tolerated. Sideeffects, such as muscle tremor, headache, palpitations, agitation and hypokalaemia, are only seen when high doses are
used [104].
Single-isomer R-albuterol is theoretically preferable (although
much more expensive) to the racemic mixture of albuterol
since the S-isomer is therapeutically inactive [104]. There is,
however, no evidence regarding the clinical effectiveness or
superiority of the use of R-albuterol compared to the racemic
mixture in this age group.
Long-acting inhaled b2-agonists
Formoterol and salmeterol have shown long-lasting bronchodilatory and bronchoprotective effects in preschool children
[99, 105]. There are no published double-blind randomised
placebo-controlled trials in preschool children on the addition
of long-acting inhaled b2-adrenergic agents to ICSs.
Inhaled corticosteroids
Treatment with ICSs may be considered for the treatment of
current symptoms, or possibly for the prevention of progression of symptoms (disease modification). Each is considered in
turn, as follows.
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Inhaled corticosteroids in treatment of symptoms of multipletrigger wheeze
A systematic review of randomised double-blind controlled
trials of inhaled glucocorticosteroids in preschool children with
multiple-trigger wheeze has shown significant improvements in
important health outcomes, including symptoms, exacerbation
rates, lung function and airway hyperresponsiveness [106]. The
treatment effect appears to be smaller than that seen in schoolage children and adults. For example, studies of ICSs in
preschool children with multiple-trigger wheeze have reported
a reduction in exacerbations by ,50% [107, 108]. Compared to
placebo, children using 200 mg?day-1 fluticasone exhibit a mean
of 5% fewer days with symptoms [106].
The dose–response relationship of ICSs in preschool children is
not entirely clear. Dose-related effects have been shown for
exacerbation rate on treatment with daily ICS doses of up to
400 mg?day-1 beclometasone equivalent (or 200 mg?day-1 fluticasone) via pressurised metered-dose inhaler (pMDI) with spacer
(pMDI-S) [107], without any further benefit from higher doses.
Comparison of 0.25, 0.5 and 1.0 mg nebulised budesonide daily,
however, showed similar improvement to that with placebo in
one study [109], whereas another suggested a dose relation in
the range 0.25–1.0 mg nebulised budesonide b.i.d. [110]. Marked
individual variations in response are seen between patients. In a
post hoc analysis of two large randomised controlled trials in
young children (aged 12–47 months), those with frequent
symptoms, aged .2 yrs and/or with a family history of asthma
showed the best response to treatment with fluticasone
(200 mg?day-1), whereas those with less frequent symptoms,
without a family history of asthma and aged ,2 yrs showed no
significant treatment effect [111]. Two recent studies using
inhaled fluticasone to treat wheezy infants and preschool
children failed to find any improvement in lung function [112,
113]. Atopic markers, such as a history of atopic dermatitis or
allergic rhinitis, did not improve the chance of responding to
ICSs [111]. However, preschool children with wheeze, selected
based on the asthma predictive index for the prediction of
persistent wheeze (including atopic dermatitis, allergic rhinitis
and eosinophilia), respond to ICSs as a group [40, 41].
Local side-effects, such as hoarseness and candidiasis, are rare
in preschool children [114], probably because medication is
usually delivered by metered-dose inhaler with spacer (MDI-S)
combination. Studies on the systemic side-effects of inhaled
steroids have yielded inconsistent results. In a 1-yr study of
200 mg?day-1 fluticasone in preschool children, height growth
was similar in the fluticasone-treated children to that in the
cromoglycate-treated children [114]. In another study, however, height growth was reduced by 1.1 cm after 2 yrs of
inhaled 200 mg?day-1 fluticasone compared with placebo [41].
The long-term consequences of inhaled steroid therapy on
growth in preschool children have not been studied. Clinically
relevant effects on adrenal function have only been observed in
children receiving high doses of ICSs (.400 mg?day-1 beclometasone equivalent) [106]. The risk of cataract was not
increased in a study of 358 children aged 1–3 yrs receiving
daily treatment with ICSs for o1 yr [114]. No other potential
systemic side-effects have been studied in preschool children.
Thus ICSs are effective in preschool children with multipletrigger wheeze, but the effect is smaller than that in older
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P.L.P. BRAND ET AL.
children, and there is some concern about the effect on height.
This justifies a more critical approach to long-term ICS use in
preschool children with multiple-trigger wheeze than in older
children and adults with asthma. Many clinicians tend first to
give a trial of ICS for a period of ,3 months. If there is no
improvement, the treatment should not be stepped up but
stopped, and further investigations should be carried out in
order to identify the cause of symptoms. If preschool children
with multiple-trigger wheeze respond well to ICS therapy, it is
unclear whether this is due to treatment or the natural
resolution of symptoms. It is recommended, therefore, that
treatment be withdrawn in children who become (almost)
completely free of wheeze after ICS therapy. There are also
clinicians who only continue treatment with ICSs in multipletrigger wheeze if symptoms recur after withdrawal, and
respond to reintroduction of the medication.
Inhaled corticosteroids in treatment of symptoms of episodic
(viral) wheeze
The clinical benefits of ICSs for episodic (viral) wheeze are
controversial [106]. Systematic reviews have concluded that
episodic high-dose inhaled glucocorticosteroids (1,600–
3,200 mg?day-1 budesonide) provide some benefit in episodic
(viral) wheeze (with a 50% reduction in the requirement for oral
steroids, but no effect on hospitalisation rates or duration of
symptoms), but that maintenance treatment with 400 mg?day-1
beclometasone equivalent does not reduce the number or the
severity of wheezing episodes in episodic (viral) wheeze [106,
115]. It should be emphasised that the available evidence is
based on a few small trials that may be underpowered for the
detection of a treatment effect. For example, the study on the
effect of maintenance treatment with ICSs in episodic (viral)
wheeze analysed only 41 patients [116]. The most recent study,
published only in abstract form, showed that intermittent
treatment with 1.5 mg?day-1 fluticasone for f10 days for
episodic (viral) wheeze reduced the severity and duration of
symptoms but at a cost of slightly reduced height [117]. Thus,
the use of high-dose intermittent steroids in this age group
requires careful consideration.
Nasal corticosteroids to reduce episodic (viral) wheeze
Although treatment of allergic rhinitis may help to ameliorate
asthma in school-age children and adolescents, a randomised
controlled trial of nasal corticosteroids in preschool children
with recurrent wheeze failed to demonstrate any benefit [118].
Treatment of episodic (viral) wheeze in preschool children to
reduce risk of persistent wheeze during later childhood
Three randomised controlled trials (two on daily ICSs and one
on intermittent use when the child was wheezy) have shown
that use of ICSs in preschool children with episodic (viral)
wheeze does not reduce the risk of persistent wheeze at the age
of 6 yrs, and that symptoms return when steroid therapy is
discontinued [41, 119, 120].
WHEEZING DISORDERS IN PRESCHOOL CHILDREN
needed to treat 3) [121]. Although that review included several
studies in preschool children, they were not analysed
separately. A systematic review of two studies found no
evidence that parent-initiated oral corticosteroids are associated with a benefit in terms of hospital admissions,
unscheduled medical reviews, symptoms scores, bronchodilator use, parent and patient impressions, physician assessment, or days lost from work or school [122].
Leukotriene modifiers
Montelukast is the only cysteinyl leukotriene receptor antagonist licensed for the treatment of young children, at a dosage of
4 mg orally once daily. No clinically relevant side-effects have
been reported [123].
Montelukast in multiple-trigger wheeze
In two studies, montelukast provided protection against
bronchoconstriction induced by hyperventilation with cold
dry air, and improved airways hyperresponsiveness by one
doubling dose after 4 weeks, compared to placebo [124, 125].
The bronchoprotective effect was independent of concurrent
steroid treatment. In a multicentric study of 689 young children
with multiple-trigger wheeze, montelukast improved symptoms and achieved a 30% reduction in exacerbations [123]. One
recent study showed that nebulised budesonide was more
effective at reducing exacerbation rates in 2–8-yr-old children
with multiple-trigger wheeze than oral montelukast [126]. Since
preschool children were not analysed separately, it is not known
whether this difference in efficacy also applies to this age range.
Montelukast in episodic (viral) wheeze
Daily use of montelukast over a 1-yr period reduced the rate of
wheezing episodes in 549 children with episodic (viral) wheeze
by 32% compared to placebo (number needed to treat 12) [127].
A trial of intermittent montelukast, started when patients
developed signs of a common cold, compared with placebo in
220 children with episodic wheeze showed a 30% reduction in
unscheduled health visits (number needed to treat 11), but no
effect on hospitalisations, duration of episode, and b-agonist
and prednisolone use [128].
Cromones
Clinical documentation regarding sodium cromoglycate use in
preschool children is sparse and there are no reports on
infants. The Cochrane Review concluded that a beneficial effect
of cromolyn therapy in preschool children with multipletrigger wheeze could not be proven [129]. Most studies were of
poor quality, but one well-designed randomised controlled
trial found no effect on symptom scores or exacerbation
frequency in children aged 1–4 yrs with multiple-trigger
wheeze [130]. No studies have been performed with nedocromil in preschool children.
Systemic glucocorticosteroids
A systematic review of systemic corticosteroids in hospitalised
children with acute asthma found that corticosteroid-treated
children were seven times more likely to be discharged early
than placebo-treated children, and five times less likely to
relapse within 1–3 months following discharge (number
Xanthines
The Cochrane Review on the effects of xanthines (theophylline
and aminophylline) in the chronic treatment of children with
asthma, the effects on symptoms and exacerbations of wheeze
in preschool children were small and mostly nonsignificant
[131]. The studies were all small however. There have been no
good studies comparing xanthines to other medications in
preschool wheeze.
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Anticholinergic agents
In the Cochrane Review it was concluded that inhaled
ipratropium may be beneficial in older children [132], but
there is no good evidence in preschool children [133]. There are
no important side-effects when ipratropium is inhaled by
MDI-S combination.
Antihistamines
The antihistamines ketotifen and cetirizine have been studied
in preschool wheeze. In the Cochrane Review it was concluded
that children treated with ketotifen were 2.4 times as likely to
be able to reduce or stop bronchodilator treatment than those
treated with placebo. There were also less consistent benefits
with respect to asthma symptoms and exacerbations [134]. The
interpretation of these studies, however, is hampered by the
fact that the description of patients is insufficient to classify
them as having episodic (viral) wheeze or multiple-trigger
wheeze. In addition, the initial favourable reports in the 1980s
were never confirmed in later studies. There are no good
studies comparing ketotifen to other asthma medications.
Cetirizine was compared to placebo in a randomised trial in
infants with atopic dermatitis, with the aim of preventing the
development of asthma. At the age of 3 yrs, there was no
difference in wheeze prevalence between the two groups. In a
post-hoc analysis in a subgroup of patients radioallergosorbent
test-positive for cat, house dust mite or grass pollen, there
appeared to be a protective effect of cetirizine [135]. This needs
to be confirmed in further studies. There are no studies of
cetirizine in preschool children with wheeze.
Other treatment options
No studies have been performed on the effects of immunotherapy or influenza immunisation in preschool children
with wheeze.
Delivery devices
As a general principle, inhaled drug delivery is preferable to
the oral and parenteral routes, in order to provide rapid relief
of symptoms and minimise systemic side-effects. Inhalation
therapy in preschool children is hampered by numerous
factors, including narrower airways, increased turbulence,
deposition high in the respiratory tree, and lack of cooperation
and coordination. Although there is anecdotal evidence
suggesting that some preschool children may be able to use
dry powder inhalers effectively and reliably [136], there is
consensus among experts that these devices should not be
used in preschool children because they lack the ability to
generate sufficiently high inspiratory flows [137]. Similarly,
pMDIs cannot be used by preschool children without the use
of a spacer device because of difficulties in the appropriate
timing of the inspiratory effort. The two inhalation systems to
be considered, therefore, are pMDI-S and nebuliser.
A systematic review has shown that the delivery of inhaled b2agonists by pMDI-S in acutely wheezy infants and preschool
children is more effective than by nebuliser; recovery was
quicker and the risk of hospital admission was reduced by 60%
[138]. There are no studies comparing the two delivery devices
for long-term management. The economic, practical and
hygienic advantages of pMDI-S over nebulisers support the
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P.L.P. BRAND ET AL.
use of pMDI-S as the preferred means of delivery of inhaled
drugs in preschool children.
Although there is no formal evidence to support this, there is
consensus that cooperative children should use a spacer device
with a mouthpiece wherever possible [137]. Noncooperative
children aged ,3 yrs should use a spacer with a face mask; a
tight face mask seal is considered important for optimal drug
delivery. Crying children are unlikely to receive any drug to
the lower airways [139].
Filter studies have shown high day-to-day variability in
delivered doses in preschool children [140]. This should be
borne in mind when prescribing therapy and judging its effects.
If a spacer is used, it should be noted that electrostatic charge
reduces MDI-S delivery. New unwashed and unprimed plastic
spacers are electrostatically charged, and, therefore, yield
reduced drug delivery [141]. This can be overcome by washing
the plastic spacer in detergent and allowing it to drip dry,
priming it with 5–10 puffs of aerosol or using a metal spacer.
There are no data on the safety of the detergent washing method
however. Since priming with aerosol is the most expensive and
wasteful method of the three, it is not recommended.
Methodological considerations
In accordance with others [106], the Task Force found it
difficult to synthesise the evidence on the efficacy of treatment
in preschool wheeze for a number of reasons. First, inclusion
criteria were commonly unclear. Studies have included
children with asthma or wheeze without further specification.
Even when inclusion criteria were specified, pooling such
studies was frequently impossible because of clinical heterogeneity or the lack of distinction of different phenotypes.
Secondly, treatment (agents, dosages and delivery devices)
differed considerably between studies. Thirdly, different outcome parameters have been studied, most of which were
neither standardised nor validated. Fourthly, the number of
studies and the number of patients enrolled was generally
quite low, especially for studies on ICSs in episodic wheeze.
Fifthly, given the fact that symptoms of wheeze in preschool
children tend to resolve spontaneously and that the most
troublesome symptoms occur episodically, adherence to
treatment by parents and caregivers is probably low, although
few studies have examined this. The one study specifically
addressing this found that parents of preschool children with
troublesome wheeze would not give their child a bronchodilator on 40% of the occasions when the child was wheezy,
even though they knew their adherence was monitored and
even though they were instructed to administer inhaled
bronchodilator when their child was wheezing [142]. Finally,
age appears to be an important effect modifier, in that the
younger the child is, the poorer the response to any treatment.
Recommendations for treatment (based on low-level
evidence unless otherwise specified)
1) Passive smoking is deleterious to preschool children with
wheeze, as at all ages (high-level evidence), and should be
firmly discouraged.
2) There is insufficient evidence on which to base recommendations for the reduction of exposure to environmental allergens
in the treatment of preschool wheezing.
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3) An educational programme using multiple teaching sessions
on causes of wheeze, recognising warning signals and
treatment should be provided to parents of wheezy preschool
children.
4) A pMDI-S combination should be used as the preferred
delivery device for inhalation therapy in preschool children
(high-level evidence).
5) In cooperative children, spacers with a mouthpiece should
probably be used.
6) In uncooperative young children, spacers with a tight-fitting
face mask should probably be used.
7) Plastic spacers should be treated with detergent before use
in order to reduce their electrostatic charge.
Acute wheezing episode
1) Inhaled short-acting b2-agonists on an as-needed basis
should be used for the symptomatic treatment of acute
wheezing in preschool children. These drugs should be used
cautiously in infants since paradoxical responses have been
reported in this age group.
WHEEZING DISORDERS IN PRESCHOOL CHILDREN
7) A trial of montelukast may be considered in preschool
children with multiple-trigger wheeze.
8) Cromones, ketotifen and xanthines are not recommended
for use in preschool children with wheeze.
9) Immunotherapy is not recommended for preschool children
with wheeze outside the setting of a randomised controlled
trial.
10) Influenza immunisation is not recommended for preschool
children with wheeze.
Maintenance treatment of episodic (viral) wheeze
1) Montelukast 4 mg once daily should probably be given for
the treatment of episodic (viral) wheeze.
2) A trial of inhaled corticosteroids may be considered in
preschool children with episodic (viral) wheeze, in particular
when episodes occur frequently or if the family history of
asthma is positive.
6) Infants aged 1–2 yrs should only be prescribed ICSs if their
symptoms are troublesome and they show a clear-cut response
to treatment.
ACKNOWLEDGEMENTS
The affiliation details of the present study’s authors are as
follows. P.L.P. Brand: Princess Amalia Children’s Clinic, Isala
Clinics, Zwolle; J.C. de Jongste: Dept of Paediatric Respiratory
Medicine, Erasmus Medical Centre/Sophia Children’s
Hospital, Rotterdam; P.J.F.M. Merkus: Dept of Paediatrics,
Division of Respiratory Medicine, Children’s Hospital,
Radboud Medical Centre Nijmegen, Nijmegen; and W.M.C.
van Aalderen: Dept of Paediatric Pulmonology, Emma
Children’s Hospital, Academic Medical Centre, Amsterdam
(all the Netherlands). E. Baraldi: Dept of Paediatrics, Unit of
Respiratory Medicine and Allergy, Unit of Neonatal Intensive
Care, University of Padua School of Medicine, Padua; A.L.
Boner and G. Piacentini: Dept of Paediatrics, G.B. Rossi
Polyclinic, Verona; F. Midulla: Dept of Paediatric Emergency,
University of Rome La Sapienza, Rome; and G.A. Rossi:
Pulmonary Disease Unit, G. Gaslini Institute, Genoa (all Italy).
H. Bisgaard: Danish Paediatric Asthma Centre, Copenhagen
University Hospital, Copenhagen, Denmark. J.A. CastroRodriguez: School of Medicine, Pontifical Catholic University
of Chile, Santiago, Chile. A. Custovic: North West Lung
Research Centre, Wythenshawe Hospital, Manchester; M.L.
Everard: University Division of Child Health, Sheffield
Children’s Hospital, Sheffield; J. Grigg: Academic Unit of
Paediatrics, Institute of Cell and Molecular Science, Barts and
The London Medical School, London; S. McKenzie: Fielden
House, Royal London Hospital, Barts and The London NHS
Trust, London; N. Wilson: Dept of Paediatrics, Royal
Brompton Hospital, London; A. Bush: Dept of Paediatric
Respirology, National Heart and Lung Institute, Royal
Brompton Hospital and Imperial College, London; W.
Lenney: Academic Dept of Child Health, University Hospital
of North Staffordshire, Stoke-on-Trent; J.Y. Paton: University
Division of Developmental Medicine, Yorkhill Hospitals,
Glasgow; P. Seddon: Royal Alexandra Children’s Hospital,
Brighton; and M. Silverman: Dept of Infection, Inflammation
and Immunology, University of Leicester, Leicester (all UK).
J. de Blic: Paediatric Pneumology and Allergology Service,
Paris Public Assistance Hospitals, Necker Hospital for Sick
Children, Paris, France. E. Eber: Respiratory and Allergic
Disease Division, Dept of Paediatrics and Adolescent
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2) Alternative routes of administration (oral and intravenous)
should not be used.
3) Single-isomer salbutamol should not be used.
4) Addition of ipratropium bromide to short-acting b2-agonists
may be considered in patients with severe wheeze.
5) A trial of oral corticosteroids should probably be given to
preschool children with acute wheeze of such severity that
they need to be admitted to hospital.
6) Parent-initiated treatment with a short course of oral
corticosteroids should not be given.
7) Although high-dose ICS therapy appears to have a small
beneficial effect in the treatment of acute wheezing in
preschool children, this treatment is not recommended because
of high cost and lack of comparison to bronchodilator therapy.
Maintenance treatment of multiple-trigger wheeze
1) ICSs at a daily dose of up to 400 mg?day-1 beclometasone
equivalent should be given for the treatment of preschool
children with multiple-trigger wheeze.
2) When the response to this treatment is poor, patients should
not be treated with higher doses but should probably be referred
to a specialist for further evaluation and investigations.
3) If response to inhaled steroids is favourable, treatment
should probably be discontinued after several weeks or
months, in order to judge whether symptoms have resolved
or whether ongoing treatment is needed.
4) Linear growth should be measured in preschool children
using ICSs.
5) Infants younger than 1 yr should probably not be prescribed
ICSs.
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Medicine, Medical University of Graz, Graz, Austria. U. Frey:
Paediatric Respiratory Medicine, Inselspital, Berne University
Hospital and University of Berne, Berne; and J.H. Wildhaber:
Dept of Paediatrics, Fribourg Bertigny Hospital, Fribourg (all
Switzerland). M. Gappa: Dept of Paediatric Pulmonology and
Neonatology, Medical University of Hanover, Hanover,
Germany. L. Garcia-Marcos: Institute of Respiratory Health,
University of Murcia, Murcia, Spain. P. Le Souëf: School of
Paediatrics and Child Health; P.D. Sly: Division of Clinical
Sciences, Telethon Institute for Child Health Research, Centre
for Child Health Research; and S. Stick: Centre for Asthma,
Allergy and Respiratory Research (all University of Western
Australia, Perth, Australia). P. Pohunek: Motol University
Hospital, Prague, Czech Republic. A. Valiulis: Vilnius City
University Hospital, Vilnius, Lithuania. G. Wennergren: Dept
of Paediatrics, Gothenburg University, Queen Silvia Children’s
Hospital, Gothenburg, Sweden. Z. Zivkovic: Centre for
Paediatric Pulmonology, Dr Dragisa Misovic Medical Centre,
Belgrade, Serbia.
REFERENCES
1 Martinez FD, Wright AL, Taussig LM, et al. Asthma and
wheezing in the first six years of life. N Engl J Med 1995;
332: 133–138.
2 Bisgaard H, Szefler S. Prevalence of asthma-like symptoms
in young children. Pediatr Pulmonol 2007; 42: 723–728.
3 Stevens CA, Turner D, Kuehni CE, Couriel JM,
Silverman M. The economic impact of preschool asthma
and wheeze. Eur Respir J 2003; 21: 1000–1006.
4 Kurukulaaratchy RJ, Fenn MH, Waterhouse LM,
Matthews SM, Holgate ST, Arshad SH. Characterization
of wheezing phenotypes in the first 10 years of life. Clin
Exp Allergy 2003; 33: 573–578.
5 Lau S, Illi S, Sommerfeld C, et al. Transient early wheeze
is not associated with impaired lung function in 7-yr-old
children. Eur Respir J 2003; 21: 834–841.
6 Global Initiative for Asthma. Global Strategy for Asthma
Management and Prevention. www.ginasthma.org/
Guidelineitem.asp??l152&l251&intId560 Date last
updated: 2007. Date last accessed: July 27, 2008.
7 British Thoracic Society, Scottish Intercollegiate
Guidelines Network.: British guideline on the management of asthma. Thorax 2003; 58: Suppl. 1, i1–i94.
8 National Heart, Lung and Blood Institute, National
Asthma Education and Prevention Program. Expert
Panel Report 3: Guidelines for the Diagnosis and
Management of Asthma. Bethesda, National Heart,
Lung and Blood Institute, 2007.
9 Kuehni CE. Phenotype specific treatment of obstructive
airways disease in infancy and childhood: new recommendations of the Swiss Paediatric Pulmonology Group.
Swiss Med Wkly 2005; 135: 95–100.
10 Monge RM, Montaner AE, Benitez MF, et al. Consensus
statement on the management of paediatric asthma.
Allergol Immunopathol (Madr ) 2006; 34: 88–101.
11 Bush A. Coughs and wheezes spread diseases: but what
about the environment? Thorax 2006; 61: 367–368.
12 Bacharier LB, Boner A, Carlsen KH, et al. Diagnosis and
treatment of asthma in childhood: a PRACTALL consensus report. Allergy 2008; 63: 5–34.
1106
VOLUME 32 NUMBER 4
P.L.P. BRAND ET AL.
13 Atkins D, Best D, Briss PA, et al. Grading quality of
evidence and strength of recommendations. BMJ 2004;
328: 1490–1494.
14 Saglani S, Malmstrom K, Pelkonen AS, et al. Airway
remodeling and inflammation in symptomatic infants
with reversible airflow obstruction. Am J Respir Crit Care
Med 2005; 171: 722–727.
15 Elphick HE, Sherlock P, Foxall G, et al. Survey of
respiratory sounds in infants. Arch Dis Child 2001; 84:
35–39.
16 Michel G, Silverman M, Strippoli MP, et al. Parental
understanding of wheeze and its impact on asthma
prevalence estimates. Eur Respir J 2006; 28: 1124–1130.
17 Elphick HE, Ritson S, Rodgers H, Everard ML. When a
‘‘wheeze’’ is not a wheeze: acoustic analysis of breath
sounds in infants. Eur Respir J 2000; 16: 593–597.
18 Cane RS, Ranganathan SC, McKenzie SA. What do
parents of wheezy children understand by ‘‘wheeze’’?
Arch Dis Child 2000; 82: 327–332.
19 Cane RS, McKenzie SA. Parents’ interpretations of
children’s respiratory symptoms on video. Arch Dis
Child 2001; 84: 31–34.
20 Levy ML, Godfrey S, Irving CS, et al. Wheeze detection:
recordings vs assessment of physician and parent. J
Asthma 2004; 41: 845–853.
21 Shields MD, Bush A, Everard ML, McKenzie SA,
Primhak R. Recommendations for the assessment and
management of cough in children. Thorax 2008; 63: Suppl.
3, iii1–iii15.
22 Silverman M. Wheezing disorders in infants and young
children. In: Silverman M, ed. Childhood Asthma and
Other Wheezing Disorders. London, Arnold, 2002;
pp. 307–332.
23 Martinez FD, Godfrey S. Wheezing Disorders in the
Preschool Child: Epidemiology, Diagnosis and Treatment.
London, Martin Dunitz, 2003.
24 Martinez FD. Genes, environments, development and
asthma: a reappraisal. Eur Respir J 2007; 29: 179–184.
25 Wenzel SE. Asthma: defining of the persistent adult
phenotypes. Lancet 2006; 368: 804–813.
26 Doull IJM, Lampe FC, Smith S, Schreiber J, Freezer NJ,
Holgate ST. Effect of inhaled corticosteroids on episodes
of wheezing associated with viral infection in school age
children: randomised double blind placebo controlled
trial. BMJ 1997; 315: 858–862.
27 Mckean MC, Hewitt C, Lambert PC, Myint S,
Silverman M. An adult model of exclusive viral wheeze:
inflammation in the upper and lower respiratory tracts.
Clin Exp Allergy 2003; 33: 912–920.
28 Papadopoulos NG, Kalobatsou A. Respiratory viruses in
childhood asthma. Curr Opin Allergy Clin Immunol 2007;
7: 91–95.
29 Hyvarinen MK, Kotaniemi-Syrjanen A, Reijonen TM,
Korhonen K, Korppi MO. Teenage asthma after severe
early childhood wheezing: an 11-year prospective followup. Pediatr Pulmonol 2005; 40: 316–323.
30 Bradley JP, Bacharier LB, Bonfiglio J, et al. Severity of
respiratory syncytial virus bronchiolitis is affected by
cigarette smoke exposure and atopy. Pediatrics 2005; 115:
e7–e14.
EUROPEAN RESPIRATORY JOURNAL
P.L.P. BRAND ET AL.
31 Horn SD, Smout RJ. Effect of prematurity on respiratory
syncytial virus hospital resource use and outcomes. J
Pediatr 2003; 143: S133–S141.
32 Lannero E, Wickman M, Pershagen G, Nordvall L.
Maternal smoking during pregnancy increases the risk
of recurrent wheezing during the first years of life
(BAMSE). Respir Res 2006; 7: 3.
33 Mertsola J, Ziegler T, Ruuskanen O, Vanto T, Koivikko A,
Halonen P. Recurrent wheezy bronchitis and viral
respiratory infections. Arch Dis Child 1991; 66: 124–129.
34 Rylander E, Eriksson M, Freyschuss U. Risk factors for
occasional and recurrent wheezing after RSV infection in
infancy. Acta Paediatr Scand 1988; 77: 711–715.
35 Simoes EA, King SJ, Lehr MV, Groothuis JR. Preterm
twins and triplets. A high-risk group for severe respiratory syncytial virus infection. Am J Dis Child 1993; 147:
303–306.
36 Bont L, van Aalderen WMC, Kimpen JLL. Long-term
consequences of respiratory syncytial virus (RSV)
bronchiolitis. Paediatr Respir Rev 2000; 1: 221–227.
37 Stein RT, Sherill D, Morgan WJ, et al. Respiratory
syncytial virus in early life and risk of wheeze and
allergy by age 13 years. Lancet 1999; 354: 541–545.
38 Lemanske RF Jr, Jackson DJ, Gangnon RE, et al.
Rhinovirus illnesses during infancy predict subsequent
childhood wheezing. J Allergy Clin Immunol 2005; 116:
571–577.
39 Castro-Rodrı́guez JA, Holberg CJ, Wright AL,
Martinez FD. A clinical index to define risk of asthma
in young children with recurrent wheezing. Am J Respir
Crit Care Med 2000; 162: 1403–1406.
40 Teper AM, Kofman CD, Szulman GA, Vidaurreta SM,
Maffey AF. Fluticasone improves pulmonary function in
children under 2 years old with risk factors for asthma.
Am J Respir Crit Care Med 2005; 171: 587–590.
41 Guilbert TW, Morgan WJ, Zeiger RS, et al. Long-term
inhaled corticosteroids in preschool children at high risk
for asthma. N Engl J Med 2006; 354: 1985–1997.
42 Taussig LM, Wright AL, Holberg CJ, Halonen M,
Morgan WJ, Martinez FD. Tucson children’s respiratory
study: 1980 to present. J Allergy Clin Immunol 2003; 111:
661–675.
43 Hess J, de Jongste JC. Epidemiological aspects of
paediatric asthma. Clin Exp Allergy 2004; 34: 680–685.
44 Goksör E, Amark M, Alm B, Gustafsson PM,
Wennergren G. Asthma symptoms in early childhood –
what happens then? Acta Paediatr 2006; 95: 471–478.
45 Wennergren G, Hansson S, Engstrom I, et al. Characteristics and prognosis of hospital-treated obstructive
bronchitis in children aged less than two years. Acta
Paediatr 1992; 81: 40–45.
46 Piippo-Savolainen E, Remes S, Kannisto S, Korhonen K,
Korppi M. Asthma and lung function 20 years after
wheezing in infancy: results from a prospective followup study. Arch Pediatr Adolesc Med 2004; 158: 1070–1076.
47 Lowe L, Murray CS, Martin L, et al. Reported versus
confirmed wheeze and lung function in early life. Arch
Dis Child 2004; 89: 540–543.
48 Elphick HE, Lancaster GA, Solis A, Majumdar A,
Gupta R, Smyth RL. Validity and reliability of acoustic
EUROPEAN RESPIRATORY JOURNAL
WHEEZING DISORDERS IN PRESCHOOL CHILDREN
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
analysis of respiratory sounds in infants. Arch Dis Child
2004; 89: 1059–1063.
Saglani S, McKenzie SA, Bush A, Payne DN. A video
questionnaire identifies upper airway abnormalities in
preschool children with reported wheeze. Arch Dis Child
2005; 90: 961–964.
Hofhuis W, van der Wiel EC, Tiddens HAWM, et al.
Bronchodilation in infants with malacia or recurrent
wheeze. Arch Dis Child 2003; 88: 246–249.
Saglani S, Nicholson AG, Scallan M, et al. Investigation of
young children with severe recurrent wheeze: any
clinical benefit? Eur Respir J 2006; 27: 29–35.
Saito J, Harris WT, Gelfond J, et al. Physiologic,
bronchoscopic, and bronchoalveolar lavage fluid findings
in young children with recurrent wheeze and cough.
Pediatr Pulmonol 2006; 41: 709–719.
Chan EY, Dundas I, Bridge PD, Healy MJ, McKenzie SA.
Skin-prick testing as a diagnostic aid for childhood
asthma. Pediatr Pulmonol 2005; 39: 558–562.
Eysink PE, ter Riet G, Aalberse RC, et al. Accuracy of
specific IgE in the prediction of asthma: development of a
scoring formula for general practice. Br J Gen Pract 2005;
55: 125–131.
Nickel R, Kulig M, Forster J, et al. Sensitization to hen’s
egg at the age of twelve months is predictive for allergic
sensitization to common indoor and outdoor allergens at
the age of three years. J Allergy Clin Immunol 1997; 99:
613–617.
Rusconi F, Patria MF, Cislaghi GU, Sideri S, Gagliardi L.
Total serum IgE and outcome in infants with recurrent
wheezing. Arch Dis Child 2001; 85: 23–25.
Koller DY, Wojnarowski C, Herkner KR, et al. High levels
of eosinophil cationic protein in wheezing infants predict
the development of asthma. J Allergy Clin Immunol 1997;
99: 752–756.
Hederos CA, Janson S, Andersson H, Hedlin G. Chest Xray investigation in newly discovered asthma. Pediatr
Allergy Immunol 2004; 15: 163–165.
Sheikh S, Stephen T, Howell L, Eid N. Gastroesophageal
reflux in infants with wheezing. Pediatr Pulmonol 1999; 28:
181–186.
Neve V, Edme JL, Devos P, et al. Spirometry in 3–5-year-old
children with asthma. Pediatr Pulmonol 2006; 41: 735–743.
Young S, Arnott J, O’Keeffe PT, Le Souëf PN, Landau LI.
The association between early life lung function and
wheezing during the first 2 yrs of life. Eur Respir J 2000;
15: 151–157.
de Gooijer A, Brand PLP, Gerritsen J, Koëter GH,
Postma DS, Knol K. Changes in respiratory symptoms
and airway reactivity after 27 years in a population-based
sample of school children. Eur Respir J 1993; 6: 848–854.
Roorda RJ, Gerritsen J, van Aalderen WMC, et al. Followup of asthma from childhood to adulthood: influence of
potential childhood risk factors on the outcome of
pulmonary function and bronchial responsiveness in
adulthood. J Allergy Clin Immunol 1994; 93: 575–584.
Sears MR, Greene JM, Willan AR, et al. A longitudinal,
population-based, cohort study of childhood asthma
followed to adulthood. N Engl J Med 2003; 349: 1414–1422.
Stern DA, Morgan WJ, Wright AL, Guerra S, Martinez FD.
Poor airway function in early infancy and lung function
VOLUME 32 NUMBER 4
1107
c
WHEEZING DISORDERS IN PRESCHOOL CHILDREN
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
1108
P.L.P. BRAND ET AL.
by age 22 years: a non-selective longitudinal cohort
study. Lancet 2007; 370: 758–764.
Turner SW, Palmer LJ, Rye PJ, et al. The relationship
between infant airway function, childhood airway
responsiveness, and asthma. Am J Respir Crit Care Med
2004; 169: 921–927.
Kim DK, Choi SH, Yu J, Yoo Y, Koh YY. Bronchial
responsiveness to methacholine and adenosine 59-monophosphate in atopic and non-atopic preschool children
with recurrent wheezing. Clin Exp Allergy 2007; 37: 15–21.
Nielsen KG, Bisgaard H. Discriminative capacity of
bronchodilator response measured with three different
lung function techniques in asthmatic and healthy
children aged 2 to 5 years. Am J Respir Crit Care Med
2001; 164: 554–559.
Dundas I, Chan EY, Bridge PD, McKenzie SA. Diagnostic
accuracy of bronchodilator responsiveness in wheezy
children. Thorax 2005; 60: 13–16.
Gabriele C, Nieuwhof EM, van der Wiel EC, et al. Exhaled
nitric oxide differentiates airway diseases in the first two
years of life. Pediatr Res 2006; 60: 461–465.
Baraldi E, Dario C, Ongaro R, et al. Exhaled nitric oxide
concentrations during treatment of wheezing exacerbation in infants and young children. Am J Respir Crit Care
Med 1999; 159: 1284–1288.
Moeller A, Franklin P, Hall GL, et al. Inhaled fluticasone
dipropionate decreases levels of nitric oxide in recurrent
wheezy infants. Pediatr Pulmonol 2004; 38: 250–255.
Straub DA, Moeller A, Minocchieri S, et al. The effect of
montelukast on lung function and exhaled nitric oxide in
infants with early childhood asthma. Eur Respir J 2005; 25:
289–294.
Straub DA, Minocchieri S, Moeller A, Hamacher J,
Wildhaber JH. The effect of montelukast on exhaled
nitric oxide and lung function in asthmatic children 2 to
5 years old. Chest 2005; 127: 509–514.
Frey U, Kuehni C, Roiha H, et al. Maternal atopic disease
modifies effects of prenatal risk factors on exhaled nitric
oxide in infants. Am J Respir Crit Care Med 2004; 170:
260–265.
Buchvald F, Baraldi E, Carraro S, et al. Measurements of
exhaled nitric oxide in healthy subjects age 4 to 17 years. J
Allergy Clin Immunol 2005; 115: 1130–1136.
Wildhaber JH, Sennhauser FH, Brand PLP. Asthma in
school-aged children and adolescents. In: Frey U,
Gerritsen J, eds. Respiratory Diseases in Infants and
Childrend. Eur Respir Mon 2006; 11: 191–216.
Saglani S, Payne DN, Zhu J, et al. Early detection of
airway wall remodelling and eosinophilic inflammation
in preschool wheezers. Am J Respir Crit Care Med 2007;
176: 858–864.
Strachan DP, Cook DG. Parental smoking and lower
respiratory illness in infancy and early childhood. Thorax
1997; 52: 905–914.
Murray CS, Poletti G, Kebadze T, et al. Study of modifiable
risk factors for asthma exacerbations: virus infection and
allergen exposure increase the risk of asthma hospital
admissions in children. Thorax 2006; 61: 376–382.
Torrent M, Sunyer J, Garcia R, et al. Early-life allergen
exposure and atopy, asthma, and wheeze up to 6 years of
age. Am J Respir Crit Care Med 2007; 176: 446–453.
82 Lowe LA, Woodcock A, Murray CS, Morris J, Simpson A,
Custovic A. Lung function at age 3 years: effect of pet
ownership and exposure to indoor allergens. Arch Pediatr
Adolesc Med 2004; 158: 996–1001.
83 Illi S, von Mutius E, Lau S, Niggemann B, Gruber C,
Wahn U. Perennial allergen sensitisation early in life and
chronic asthma in children: a birth cohort study. Lancet
2006; 368: 763–770.
84 Peroni DG, Piacentini GL, Costella S, et al. Mite avoidance
can reduce air trapping and airway inflammation in allergic
asthmatic children. Clin Exp Allergy 2002; 32: 850–855.
85 Custovic A, Wijk RG. The effectiveness of measures to
change the indoor environment in the treatment of
allergic rhinitis and asthma: ARIA update (in collaboration with GA2LEN). Allergy 2005; 60: 1112–1115.
86 Morgan WJ, Crain EF, Gruchalla RS, et al. Results of a
home-based environmental intervention among urban
children with asthma. N Engl J Med 2004; 351: 1068–1080.
87 Gore RB, Custovic A. Is allergen avoidance effective? Clin
Exp Allergy 2002; 32: 662–666.
88 Mesters I, Pieterse M, Meertens R. Pediatric asthma, a
qualitative and quantitative approach to needs assessment. Patient Educ Couns 1991; 17: 23–34.
89 Wolf FM, Guevara JP, Grum CM, Clark NM, Cates CJ.
Educational interventions for asthma in children.
Cochrane Database Syst Rev 2003; Issue 4: CD000326.
90 Wilson SR, Latini D, Starr NJ, et al. Education of parents
of infants and very young children with asthma: a
developmental evaluation of the Wee Wheezers program.
J Asthma 1996; 33: 239–254.
91 Brown JV, Bakeman R, Celano MP, Demi AS,
Kobrynski L, Wilson SR. Home-based asthma education
of young low-income children and their families. J Pediatr
Psychol 2002; 27: 677–688.
92 Mesters I, Meertens R, Kok G, Parcel GS. Effectiveness of
a multidisciplinary education protocol in children with
asthma (0–4 years) in primary health care. J Asthma 1994;
31: 347–359.
93 Stevens CA, Wesseldine LJ, Couriel JM, Dyer AJ,
Osman LM, Silverman M. Parental education and guided
self-management of asthma and wheezing in the preschool child: a randomised controlled trial. Thorax 2002;
57: 39–44.
94 Holzheimer L, Mohay H, Masters IB. Educating young
children about asthma: comparing the effectiveness of a
developmentally appropriate asthma education video
tape and picture book. Child Care Health Dev 1998; 24:
85–99.
95 Holmgren D, Bjure J, Engstrom I, Sixt R, Sten G,
Wennergren G. Transcutaneous blood gas monitoring
during salbutamol inhalations in young children with acute
asthmatic symptoms. Pediatr Pulmonol 1992; 14: 75–79.
96 Kraemer R, Frey U, Sommer CW, Russi E. Short-term
effect of albuterol, delivered via a new auxiliary device, in
wheezy infants. Am Rev Respir Dis 1991; 144: 347–351.
97 Conner WT, Dolovich MB, Frame RA, Newhouse MT.
Reliable salbutamol administration in 6- to 36-month-old
children by means of a metered dose inhaler and
Aerochamber with mask. Pediatr Pulmonol 1989; 6:
263–267.
VOLUME 32 NUMBER 4
EUROPEAN RESPIRATORY JOURNAL
P.L.P. BRAND ET AL.
98 Pool JB, Greenough A, Gleeson JG, Price JF. Inhaled
bronchodilator treatment via the nebuhaler in young
asthmatic patients. Arch Dis Child 1988; 63: 288–291.
99 Nielsen KG, Bisgaard H. Bronchodilation and bronchoprotection in asthmatic preschool children from formoterol administered by mechanically actuated dry-powder
inhaler and spacer. Am J Respir Crit Care Med 2001; 164:
256–259.
100 Avital A, Godfrey S, Schachter J, Springer C. Protective
effect of albuterol delivered via a spacer device
(Babyhaler) against methacholine induced bronchoconstriction in young wheezy children. Pediatr Pulmonol
1995; 17: 281–284.
101 Prendiville A, Green S, Silverman M. Airway responsiveness in wheezy infants: evidence for functional beta
adrenergic receptors. Thorax 1987; 42: 100–104.
102 Fox GF, Marsh MJ, Milner AD. Treatment of recurrent
acute wheezing episodes in infancy with oral salbutamol
and prednisolone. Eur J Pediatr 1996; 155: 512–516.
103 Browne GJ, Penna AS, Phung X, Soo M. Randomised trial
of intravenous salbutamol in early management of acute
severe asthma in children. Lancet 1997; 349: 301–305.
104 Skoner DP, Greos LS, Kim KT, Roach JM, Parsey M,
Baumgartner RA. Evaluation of the safety and efficacy of
levalbuterol in 2–5-year-old patients with asthma. Pediatr
Pulmonol 2005; 40: 477–486.
105 Primhak RA, Smith CM, Yong SC, et al. The bronchoprotective effect of inhaled salmeterol in preschool children:
a dose-ranging study. Eur Respir J 1999; 13: 78–81.
106 Kaditis AG, Winnie G, Syrogiannopoulos GA. Antiinflammatory pharmacotherapy for wheezing in preschool children. Pediatr Pulmonol 2007; 42: 407–420.
107 Bisgaard H, Gillies J, Groenewald M, Maden C, an
International Study Group, The effect of inhaled fluticasone propionate in the treatment of young asthmatic
children. A dose comparison study. Am J Respir Crit Care
Med 1999; 160: 126–131.
108 de Blic J, Delacourt C, Le Bourgeois M, et al. Efficacy of
nebulized budesonide in treatment of severe infantile
asthma: a double-blind study. J Allergy Clin Immunol
1996; 98: 14–20.
109 Baker JW, Mellon M, Wald J, Welch M, Cruz-Rivera M,
Walton-Bowen K. A multiple-dosing, placebo-controlled
study of budesonide inhalation suspension given once or
twice daily for treatment of persistent asthma in young
children and infants. Pediatrics 1999; 103: 414–421.
110 Shapiro G, Mendelson L, Kraemer MJ, Cruz-Rivera M,
Walton-Bowen K, Smith JA. Efficacy and safety of
budesonide inhalation suspension (Pulmicort Respules)
in young children with inhaled steroid-dependent, persistent asthma. J Allergy Clin Immunol 1998; 102: 789–796.
111 Roorda RJ, Mezei G, Bisgaard H, Maden C. Response of
preschool children with asthma symptoms to fluticasone
propionate. J Allergy Clin Immunol 2001; 108: 540–546.
112 Hofhuis W, van der Wiel EC, Nieuwhof EM, et al.
Efficacy of fluticasone propionate on lung function and
symptoms in wheezy infants. Am J Respir Crit Care Med
2005; 171: 328–333.
113 Schokker S, Kooi EM, de Vries TW, et al. Inhaled
corticosteroids for recurrent respiratory symptoms in
EUROPEAN RESPIRATORY JOURNAL
WHEEZING DISORDERS IN PRESCHOOL CHILDREN
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
preschool children: randomized controlled trial. Pulm
Pharmacol Ther 2008; 21: 88–97.
Bisgaard H, Allen D, Milanowski J, Kalev I, Willits L,
Davies P. Twelve-month safety and efficacy of inhaled
fluticasone propionate in children aged 1 to 3 years with
recurrent wheezing. Pediatrics 2004; 113: e87–e94.
McKean M, Ducharme F. Inhaled steroids for episodic
viral wheeze of childhood. Cochrane Database Syst Rev
2000; Issue 1: CD001107.
Wilson N, Sloper K, Silverman M. Effect of continuous
treatment with topical corticosteroid on episodic viral
wheeze in preschool children. Arch Dis Child 1995; 72:
317–320.
Ducharme FM, Lemire C, Nova FJ, et al. Randomized
controlled trial of intermittent high dose fluticasone versus
placebo in young children with viral-induced asthma. Am
J Respir Crit Care Med 2007; 175: Suppl. 1, A958.
Silverman M, Wang M, Hunter G, Taub N. Episodic viral
wheeze in preschool children: effect of topical nasal
corticosteroid prophylaxis. Thorax 2003; 58: 431–434.
Bisgaard H, Hermansen MN, Loland L, Halkjaer LB,
Buchvald F. Intermittent inhaled corticosteroids in
infants with episodic wheezing. N Engl J Med 2006; 354:
1998–2005.
Murray CS, Woodcock A, Langley SJ, Morris J,
Custovic A. Secondary prevention of asthma by the use
of inhaled fluticasone propionate in wheezy infants
(IFWIN): double-blind, randomised, controlled study.
Lancet 2006; 368: 754–762.
Smith M, Iqbal S, Elliott TM, Everard M, Rowe BH.
Corticosteroids for hospitalised children with acute
asthma. Cochrane Database Syst Rev 2003; Issue 1:
CD002886.
Vuillermin P, South M, Robertson C. Parent-initiated oral
corticosteroid therapy for intermittent wheezing illnesses
in children. Cochrane Database Syst Rev 2006; Issue 3:
CD005311.
Knorr B, Franchi LM, Bisgaard H, et al. Montelukast, a
leukotriene receptor antagonist, for the treatment of
persistent asthma in children aged 2 to 5 years.
Pediatrics 2001; 108: e48.
Bisgaard H, Nielsen KG. Bronchoprotection with a
leukotriene receptor antagonist in asthmatic preschool
children. Am J Respir Crit Care Med 2000; 162: 187–190.
Hakim F, Vilozni D, Adler A, Livnat G, Tal A, Bentur L.
The effect of montelukast on bronchial hyperreactivity in
preschool children. Chest 2007; 131: 180–186.
Szefler SJ, Baker JW, Uryniak T, Goldman M, Silkoff PE.
Comparative study of budesonide inhalation suspension
and montelukast in young children with mild persistent
asthma. J Allergy Clin Immunol 2007; 120: 1043–1050.
Bisgaard H, Zielen S, Garcia-Garcia ML, et al.
Montelukast reduces asthma exacerbations in 2- to 5year-old children with intermittent asthma. Am J Respir
Crit Care Med 2005; 171: 315–322.
Robertson CF, Price D, Henry R, et al. Short-course
montelukast for intermittent asthma in children: a
randomized controlled trial. Am J Respir Crit Care Med
2007; 175: 323–329.
van der Wouden JC, Tasche MJ, Bernsen RM, Uijen JH, de
Jongste JC, Ducharme FM. Inhaled sodium cromoglycate
VOLUME 32 NUMBER 4
1109
c
WHEEZING DISORDERS IN PRESCHOOL CHILDREN
130
131
132
133
134
135
1110
for asthma in children. Cochrane Database Syst Rev 2003;
Issue 3: CD002173.
Tasche MJA, van der Wouden JC, Uijen JHJM,
Bernsen RM, van Suijlekom-Smit LWA, de Jongste JC.
Randomised placebo-controlled trial of inhaled sodium
cromoglycate in 1–4 year-old children with moderate
asthma. Lancet 1997; 350: 1060–1064.
Seddon P, Bara A, Ducharme FM, Lasserson TJ. Oral
xanthines as maintenance treatment for asthma in
children. Cochrane Database Syst Rev 2006; Issue 1:
CD002885.
McDonald NJ, Bara AI. Anticholinergic therapy for
chronic asthma in children over two years of age.
Cochrane Database Syst Rev 2003; Issue 1: CD003535.
Everard ML, Bara A, Kurian M, Elliott TM, Ducharme F,
Mayowe V. Anticholinergic drugs for wheeze in children
under the age of two years. Cochrane Database Syst Rev
2005; Issue 3: CD001279.
Schwarzer G, Bassler D, Mitra A, Ducharme FM, Forster J.
Ketotifen alone or as additional medication for long-term
control of asthma and wheeze in children. Cochrane
Database Syst Rev 2004; Issue 1: CD001384.
Warner JO. A double-blind, randomized, placebo-controlled trial of cetirizine in preventing the onset of asthma
in children with atopic dermatitis: 18 months’ treatment
VOLUME 32 NUMBER 4
P.L.P. BRAND ET AL.
136
137
138
139
140
141
142
and 18 months’ posttreatment follow-up. J Allergy Clin
Immunol 2001; 108: 929–937.
Agertoft L, Pedersen S. Importance of training for correct
Turbuhaler use in preschool children. Acta Paediatr 1998;
87: 842–847.
O’Callaghan C, Barry PW. How to choose delivery
devices for asthma. Arch Dis Child 2000; 82: 185–187.
Castro-Rodriguez JA, Rodrigo GJ. b-agonists through
metered-dose inhaler with valved holding chamber
versus nebulizer for acute exacerbation of wheezing or
asthma in children under 5 years of age: a systematic
review with meta-analysis. J Pediatr 2004; 145: 172–177.
Iles R, Lister P, Edmunds AT. Crying significantly
reduces absorption of aerosolized drug in infants. Arch
Dis Child 1999; 81: 163–165.
Janssens HM, Devadason SG, Hop WCJ, Le Souëf PN, de
Jongste JC, Tiddens HAWM. Variability of aerosol
delivery via spacer devices in young asthmatic children
in daily life. Eur Respir J 1999; 13: 787–791.
Janssens HM, Heijnen EMEW, de Jong VM, et al. Aerosol
delivery from spacers in wheezy infants: a daily life
study. Eur Respir J 2000; 16: 850–856.
Ferguson AE, Gibson NA, Aitchison TC, Paton JY.
Measured bronchodilator use in preschool children with
asthma. BMJ 1995; 310: 1161–1164.
EUROPEAN RESPIRATORY JOURNAL